The somatosensory system mediates a variety of sensations including proprioception, touch, temperature, and pain through receptors that are dispersed throughout the body. Pain perception is important; it alerts us to the fact that indicates that a tissue has been, or to be injured. Chronic pain, however, can have devastating effects on the quality of life. It has been estimated that in the United States alone, about 2 million people are incapacitated by pain at any given time. It is important to distinguish between nociception, i.e. the activation of pain receptors or nociceptors and pain perception, i.e. the conscious unpleasant experience of pain. Not every nociceptive signal is painful, even though it may activate a motoric reflex. How painful a stimulus is, is strongly dependent on the circumstances. Inflamed tissue, for example, is particularly pain sensitive (hyperalgesia) and normally innocuous stimuli may be experienced as pain (allodynea). Psychological factors are important as well. Stressful or dangerous situations, such as combat, often lead to a reduction in pain sensitivity. On the other hand, the expectation of pain (e.g. before a dental procedure) may lead to increased sensitivity. We have generated mice with targeted mutations in the pre-proenkephalin gene (Penk2) and the neurokinin 1 gene (Tac1). These animals develop normally and have no obvious abnormalities in their nocicpetive neuronal pathways. However, both genetic perturbations lead to abnormal behavioral responses in nociceptive tests. Penk2 knockout mice show increased pain sensitivity in the hotplate assay and abnormal pain responses in the formalin test. In contrast, mice that are homozygous for the mutation in the Tac1 gene, exhibit decreased pain sensitivity in the hotplate test and do not show any discernible pain responses in the formalin test. Both of the mutant mouse strains have normal nociceptive responses in the tail flick assay. Thus, mutations in the Tac1 and enkephalin-genes (Penk2), had opposite effects and it appears that the enkephalin and Tac1-derived neuropeptides modulate nociceptive inputs antagonistically and thus influence whether or not a nociceptive stimulus is experienced as pain.